title: Design and synthesis of conformationally restricted capsaicin analogues based in the 1, 3, 4-thiadiazole heterocycle reveal a novel family of transient receptor potential vanilloid 1 (TRPV1) antagonists.
abstract: 4-hydroxy-3-methoxybenzaldehyde was used as starting material to obtain a number of 1, 3, 4-thiadiazole alkylamide derivatives. The pharmacological properties of these conformationally restricted capsaicin analogues were evaluated on HEK-293T cells transiently expressing TRPV1 receptor. By means of a highthroughput calcium imaging assay we find that 1, 3, 4-thiadiazoles (compounds 8-15) act as potent antagonists of the capsaicin receptor, inhibiting both, the capsaicin- and temperature-dependent activation. Docking studies suggested a different binding orientation on the vanilloid binding site when compared with capsaicin analogues, such as 5-iodononivamide. Overall, our studies suggest that 1, 3, 4-thiadiazoles interact with capsaicin's binding region of the receptor, although using a different set of interactions within the vanilloid binding pocket.
authors.affiliation: Department of Organic Chemistry, Faculty of Chemical Sciences, University of Concepcion, Edmundo Larenas 160C, Concepción 1430000, Chile.
authors.forename: Carolyne Lespay
authors.initials: CL
authors.lastname: Rebolledo
authors.forename: Pamela
authors.initials: P
authors.lastname: Sotelo-Hitschfeld
authors.forename: Sebastián
authors.initials: S
authors.lastname: Brauchi
authors.forename: Miguel Zárraga
authors.initials: MZ
authors.lastname: Olavarría
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives*; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D051381:Rats; D055672:Static Electricity; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D050916:TRPV Cation Channels; D013830:Thiadiazoles; C493922:Trpv1 protein, rat; D002211:Capsaicin
keywords: 1, 3, 4-thiadiazole; AOYSLMGJSODPFL-UHFFFAOYSA-N; Antagonist activity; BSPCBZUBIMXXLE-UHFFFAOYSA-N; CLYGEOIHYUCALV-UHFFFAOYSA-N; CMJXYVMALHZRQM-UHFFFAOYSA-N; Capsaicin analogues; DRG; DYNLINSCGMXBCC-UHFFFAOYSA-N; IITOGCQJPPIAMI-UHFFFAOYSA-N; KWTNWXUICRTCLY-UHFFFAOYSA-N; OSDVZVIOEZHZRA-UHFFFAOYSA-N; Restriction conformational; Rf; TLC; TRPV1 receptor; VMUGFJHHAQTKCY-UHFFFAOYSA-N; VTEBRQCNVDRVGM-UHFFFAOYSA-N; cTRPV1; chicken TRPV1; dorsal root ganglion; rTRPV1; rat TRPV1; retention factor; thin layer chromatography